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  • 1
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    Activating mutations in ALK provide a therapeutic target in neuroblastoma (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-10-17
    Description: Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587486/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587486/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉George, Rani E -- Sanda, Takaomi -- Hanna, Megan -- Frohling, Stefan -- Luther, William 2nd -- Zhang, Jianming -- Ahn, Yebin -- Zhou, Wenjun -- London, Wendy B -- McGrady, Patrick -- Xue, Liquan -- Zozulya, Sergey -- Gregor, Vlad E -- Webb, Thomas R -- Gray, Nathanael S -- Gilliland, D Gary -- Diller, Lisa -- Greulich, Heidi -- Morris, Stephan W -- Meyerson, Matthew -- Look, A Thomas -- CA21765/CA/NCI NIH HHS/ -- CA69129/CA/NCI NIH HHS/ -- K08 NS047983/NS/NINDS NIH HHS/ -- K08 NS047983-03/NS/NINDS NIH HHS/ -- K08 NS047983-04/NS/NINDS NIH HHS/ -- K08 NS047983-05/NS/NINDS NIH HHS/ -- England -- Nature. 2008 Oct 16;455(7215):975-8. doi: 10.1038/nature07397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923525" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Enzyme Activation/genetics ; Genome, Human/genetics ; Humans ; In Situ Hybridization, Fluorescence ; In Situ Nick-End Labeling ; Mice ; Mutation/*genetics ; Neuroblastoma/enzymology/*genetics/pathology/*therapy ; Polymorphism, Single Nucleotide/genetics ; Protein Structure, Tertiary/genetics ; Protein-Tyrosine Kinases/*antagonists & inhibitors/chemistry/*genetics/metabolism ; Receptor Protein-Tyrosine Kinases ; Sequence Analysis, DNA
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Targeting transcription regulation in cancer with a covalent CDK7 inhibitor (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-07-22
    Description: Tumour oncogenes include transcription factors that co-opt the general transcriptional machinery to sustain the oncogenic state, but direct pharmacological inhibition of transcription factors has so far proven difficult. However, the transcriptional machinery contains various enzymatic cofactors that can be targeted for the development of new therapeutic candidates, including cyclin-dependent kinases (CDKs). Here we present the discovery and characterization of a covalent CDK7 inhibitor, THZ1, which has the unprecedented ability to target a remote cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7. Cancer cell-line profiling indicates that a subset of cancer cell lines, including human T-cell acute lymphoblastic leukaemia (T-ALL), have exceptional sensitivity to THZ1. Genome-wide analysis in Jurkat T-ALL cells shows that THZ1 disproportionally affects transcription of RUNX1 and suggests that sensitivity to THZ1 may be due to vulnerability conferred by the RUNX1 super-enhancer and the key role of RUNX1 in the core transcriptional regulatory circuitry of these tumour cells. Pharmacological modulation of CDK7 kinase activity may thus provide an approach to identify and treat tumour types that are dependent on transcription for maintenance of the oncogenic state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244910/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244910/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kwiatkowski, Nicholas -- Zhang, Tinghu -- Rahl, Peter B -- Abraham, Brian J -- Reddy, Jessica -- Ficarro, Scott B -- Dastur, Anahita -- Amzallag, Arnaud -- Ramaswamy, Sridhar -- Tesar, Bethany -- Jenkins, Catherine E -- Hannett, Nancy M -- McMillin, Douglas -- Sanda, Takaomi -- Sim, Taebo -- Kim, Nam Doo -- Look, Thomas -- Mitsiades, Constantine S -- Weng, Andrew P -- Brown, Jennifer R -- Benes, Cyril H -- Marto, Jarrod A -- Young, Richard A -- Gray, Nathanael S -- CA109901/CA/NCI NIH HHS/ -- CA178860-01/CA/NCI NIH HHS/ -- HG002668/HG/NHGRI NIH HHS/ -- P01 NS047572/NS/NINDS NIH HHS/ -- P01 NS047572-10/NS/NINDS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-04/CA/NCI NIH HHS/ -- R01 CA179483/CA/NCI NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R21 CA178860/CA/NCI NIH HHS/ -- T32 GM008042/GM/NIGMS NIH HHS/ -- U54 HG006097/HG/NHGRI NIH HHS/ -- U54 HG006097-02/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Jul 31;511(7511):616-20. doi: 10.1038/nature13393. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [4]. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3]. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; Department of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA. ; 1] Department of Medicine Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129, USA [2] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore. ; Chemical Kinomics Research Center, Korea Institute of Science and Technology, 39-1, Hawolgok-dong, Seongbuk-gu, Seoul 136-791, Korea, and KU-KIST Graduate School of Converging Science and Technology, 145, Anam-ro, Seongbuk-gu, Seoul 136-713, Korea. ; Daegu-Gyeongbuk Medical Innovation Foundation, 2387 dalgubeol-daero, Suseong-gu, Daegu 706-010, Korea. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115 USA. ; 1] Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043025" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Core Binding Factor Alpha 2 Subunit/metabolism ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Cysteine/metabolism ; Enzyme Inhibitors/*pharmacology ; Gene Expression Regulation, Neoplastic/*drug effects ; Humans ; Jurkat Cells ; Phenylenediamines/*pharmacology ; Phosphorylation/drug effects ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*enzymology ; Pyrimidines/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-15
    Description: In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720521/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720521/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mansour, Marc R -- Abraham, Brian J -- Anders, Lars -- Berezovskaya, Alla -- Gutierrez, Alejandro -- Durbin, Adam D -- Etchin, Julia -- Lawton, Lee -- Sallan, Stephen E -- Silverman, Lewis B -- Loh, Mignon L -- Hunger, Stephen P -- Sanda, Takaomi -- Young, Richard A -- Look, A Thomas -- 1R01CA176746-01/CA/NCI NIH HHS/ -- 5P01CA109901-08/CA/NCI NIH HHS/ -- 5P01CA68484/CA/NCI NIH HHS/ -- CA114766/CA/NCI NIH HHS/ -- CA120215/CA/NCI NIH HHS/ -- CA167124/CA/NCI NIH HHS/ -- CA29139/CA/NCI NIH HHS/ -- CA30969/CA/NCI NIH HHS/ -- CA98413/CA/NCI NIH HHS/ -- CA98543/CA/NCI NIH HHS/ -- P01 CA109901/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2014 Dec 12;346(6215):1373-7. doi: 10.1126/science.1259037. Epub 2014 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6BT, UK. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA. ; Department of Pediatrics, Benioff Children's Hospital, University of California San Francisco, CA 94143, USA. ; Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO 80045, USA. ; Cancer Science Institute of Singapore, National University of Singapore, and Department of Medicine, Yong Loo Lin School of Medicine, 117599, Singapore. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. thomas_look@dfci.harvard.edu young@wi.mit.edu. ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Division of Pediatric Hematology-Oncology, Boston Children's Hospital, MA 02115, USA. thomas_look@dfci.harvard.edu young@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25394790" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Base Sequence ; Basic Helix-Loop-Helix Transcription Factors/*genetics ; Binding Sites ; Cell Line, Tumor ; *DNA, Intergenic ; *Enhancer Elements, Genetic ; *Gene Expression Regulation, Neoplastic ; Histones/metabolism ; Humans ; *INDEL Mutation ; Molecular Sequence Data ; *Mutation ; Oncogenes ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Protein Interaction Domains and Motifs ; Proto-Oncogene Proteins/*genetics ; Proto-Oncogene Proteins c-myb/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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